2-thio-3, 3-dihydrocarbon 4-oxo-tetrahydro pyridines and preparation thereof



2-THIO-3,3-D1HYDROCARBON 4 OX TETRAHY- DRO PYRIDINES AND PREPARATIONTHEREOF August Hans Lutz, Basel, Switzerland, assiguor to Hoffmann-LaRoche Inc., Nutley, N. J., a corporation of New Jersey No Drawing.Application November 18, 1953, Serial No. 392,998

Claims priority, application Switzerland December 4, 1952 8 Claims. (Cl.260-4943) The present invention concerns sulfur containing pyridones ofthe general formula wherein R1 and R2 stand for hydrocarbon radicalscontaining 1-4 carbon atoms more particularly lower alkyl and alkenylradicals, such as methyl, ethyl, propyl butyl, vinyl, allyl groups.These sulfur containing pyridones are characterized by a strong, butonly short hypnotic ction. Especially valuable is2-thio-3-methyl-3-ethyl-4- oxo-1,2,3,4-tetrahydropyridine.

The novel compounds of the above formula are of pale yellow coloration,they are only difiicultly soluble in water, but easily soluble in theusual-organicsolvents, such as alcohol, ether, benzene, dioxan. They arealso soluble in aqueous alkaline solutions, the color becoming darker,and may be precipitated therefrom by means of acids, the color gettinglighter again.

The invention provides also a process for the manufacture of the abovesulfur containing pyridones, which process comprises condensing ana,a-dihydrocarbyl-acetacetonitrile with a formic acid ester in thepresence of an alkaline condensing agent to produce the corresponding-hydroXy-methylene compound, treating the latter with ammonia to formthe 'y-amino-methylene compound, cyclizing the same by means of analkaline condensing agent and treating the cyclization product withhydrogen sulfide or a hydrogen sulfide producing agent.

The a,ci-dihydrocarbyl-acetacetonitriles may be ob tained by alkylationor alkenylation of the u-alkyl-acetacetonitriles described by E. Mohr(Journal fiir praktische Chernie (2), volume 57 [1907], page 549, andvolume 90 [1914], page 189). The alkylation may be carried out withalkenyl or alkyl halides according to methods usually employed for thealkylation of a-alkyl-acetacetic esters. The ot,a dihydrocarbyl--hydroxymethyleneacetacetonitriles are obtained preferably by reactionof the corresponding nitriles with a formic acid ester in an inertorganic solvent, such as benzene, toluene or diethylcarbonate, in thepresence of an alkaline condensing agent, such as sodium metal,potassium metal or sodium alcoholate.

The a,u-dihydrocarbyl-acetacetonitriles, which are difficultly solublein water, do not form any salts with aqueous alkali solutions and mayeasily be separated from the a, dihydrocarbyl-'-hydroxymethylene-acetacetoni triles formed, which themselves are easilysoluble in aqueous alkali solutions. The latter may then be treated withammonia and ammonium chloride to produce thea,u-dihydrocarbyl-v-aminomethylene compounds, which are difiicultlysoluble in aqueous solution.

The a,u-dihydrocarbyl-y-aminomethylene-acetacetoni- 2,740,790 PatentedApr. 3, 1956 ice A triles, as obtained above, may be cyclized withalkaline condensing agents, for example alkali alcoholate, the cyclizingreaction being suitably conducted in an organic solvent, suchasmethanol. When reacting the cyclization product with hydrogen sulfideor with a hydrogen sulfide I producing agent, such as phosphoruspentasulfide, then the desired 2-thio-3,3-dihydrocarbyl-4-oxo-1,2,3,4-tetra1 hydropyridiues are obtained.

Example 1 To a solution of 23 parts by weight of sodium in 500 parts byvolume of dry alcohol is added a mixture of 97 parts by Weight of2-cyanobutanone-3 (E. Mohr, Journal fiir praktische Chemie (2), volume90 [1914], page 189 [boiling pointis mm. 78 C.]) and 109 parts by weightof ethyl bromide and the mixture is stirred at 50 C. for 16 hours. Themain part of the alcohol is distilled oif, water is added to the residueand the u-cthyl-a-methylacetacetonitrile formed is separated. This oil,which is insoluble in alkalis, boils without being decomposed between 80and 82 C./ 14 mm.

125 parts by weight of ot-ethyl-a-methyl-acetacetonitrile and parts byweight of formic acid methylester are added to a suspension of 24 partsby weight of sodium in 800 parts by volume of toluene and the mixture isstirred at 20 C. for 16 hours. The sodium salt ofa-ethyla-methyl-y-hydroxymethylene-acetacetonitrile formed is dissolvedwith water, separated and directly converted into the aminomethylenecompound by the addition of ammonium chloride and ammonia. Thea-ethyl-a-methyl- 'y-aminomethylene-acetacetonitrile, which in dilutedammonia solution is difficultly soluble, is extracted with benzene; thebenzene extract is then dried and evaporated in vacuo. The remaining oilmay be purified by distillation in high vacuo (boiling pointons mm. 106C.).

152 parts by weight of a-ethyl-a-methyl-y-aminomethyleneacetacetonitrileare reacted with a sodium alcoholate solution, prepared from 30 parts byweight of sodium and 500 parts by volume of alcohol, and allowed tostand for 12 hours. Then 80 parts by weight of hydrogen sulfide areintroduced, the solution becoming warm. Once the reaction is completed,125 parts by volume of 37 per cent hydrochloric acid are added dropwise,hydrogen sulfide being thereby liberated. The dark colored reactionproduct is filtered through charcoal. Upon adding dropwise 500 parts byvolume of water, the 2-thio3-ethyl-3-methyl-4-oxo-1,2,3,4-tetrahydropyridine formed precipitates in yellow crystals.After a recrystallization from methanol, the crystals melt at 113-1 14C.

Example 2 97 parts by weight of 2-cyanobutanone-3 are dissolved in 1000parts by volume of l N sodium hydroxide solution, 0.1 part by weight ofcopper powder are added and, while stirring, the mixture is reacted with121 parts by weight of allyl bromide. Thea-allyl-u-methyl-acetacetonitrile, which i difficultly soluble in water,is separated ofi and distilled in vacuo. The boiling point of thecolorless oil is 80-85 C./ 12 mm.

137 parts by weight of a-allyl-a-methyl-acetacetonitrile are dissolvedin 600 parts by volume of methanol and shaken at room temperature withhydrogen under atmoa pheric pressure or under slightly elevated pressurein the presence of a catalyst, such a palladium charcoal. After 1 mol ofhydrogen is absorbed, the hydrogenation is interrupted. After removal ofthe catalyst and of the solvent, thea-npropyl-a-methyl-acetacetonitrile, which boils between 90 and C./ 12mm., is obtained.

139 parts by weight of wn-propyl-a-methyl-acetacetonitrile are mixedwith 90 parts by weight of formic acid ethylester and added dropwise atroom temperature to a suspension of 24 parts by weight of sodium in 600parts by weight of benzene. After 12 hours stirring, the solution isextracted with 500 parts of water and the aqueous layer is separated. 60parts by weight of ammonium chloride and 30 parts by volume of 25 percent aqueous ammonia are added thereto, whereupon the mixture is stirredat 60 C. for 2 hours. The precipitated OL-R-propyl-a-met11yl-'y-aminomethylene-acetacetonitrile i extracted twicewith 200 parts by volume of benzene and the extracts are concentrated invacuo to dryness to yield the pure compound.

The 2-thio 3 n-propyl-3-methyl-4-oxo-1,2,3,4-tetrahydropyridine isprepared from the above compound in a manner analogous to that describedin Example 1. The melting point of the product, after recrystallizationfrom methanol, is 117-118 C.

The corresponding 2 thio 3 allyl-3-methyl-4-oxo-1,2,3,4-tetrahydropyridine, which may be prepared according to the sameprocedure, is isolated as an oil.

Example 3 As described in Example 1, a-ethyl-acetacetonitrile (E. Mohr,Journal fiir praktisehe Chemie, (2), volume 75, [1907], page 549) isreacted with ethyl bromide in sodium alcoholate solution. The c,a-diethyl-acetacetonitrile formed boils at IOU-102 C./14 mm.

The above a,a-diethyl-acetacetonitrile can be converted in the samemanner as described in Example 1 into thea,ot-diethyl--y-aminomethylene-acetacetonitrile, which boils between 137and 140 C./0.l mm.

160 parts by weight of vea-diethyl-'y-amiuomethylencacetacetonitrile areheated with a solution of 24 parts by weight of sodium in 500 parts byvolume of absolute alcohol, whereupon 50 parts by weight of hydrogensulfide are introduced. After working up according to Example 1,2-thio-3,3-diethyl-4-oxo-1,2,3,4-tetrahydropyridine is obtained in theform of yellow crystals of melting point 141- 142 C.

I claim:

.1. A compound selected from the group consisting of2-thio-3,3-dihydrocarbyl 4 oxo-1,2,3,4-tetrahydropyridines, the ammoniumand alkali metal salts thereof; said hydrocarbyl being a monovalentacyclic hydrocarbon radical containing from 1 to 4 carbon atoms.

2. A 2-thio-3,3-di(lower alkyl)-4-oxo-1,2,3,4-tetrahydropyridine.

3. A 2-thio-3(lower 1,2,3,4-tetrahydropyridine.

4. 2-thio-3-methyl 3 ethyl-4-oxo-1,2,3,4-tetrahydropyridine.

5. A process which comprises condensing ana,a-dihydorcarbyl-acetacetonitrile with a lower formic acid ester in thepresence of an alkaline condensing agent to produce the correspondingor,a-dihydrocarbyl-'yhydroxymethyleneacetacetonitrile, treating thelatter with ammonia to form (1,0: dihydrocarbyl '7aminornethylene-acetacetonitrile, cyclizing the same by mean of analkaline condensing agent and treating the cyclization product with acompound selected from a group consisting of hydrogen sulfide and ahydrogen sulfide producing agent, to produce a 2-thio-3,3-dihydrocarbyl-4-oxo-1,2,3,4 tetrahydropyridine; saidhydrocarbyl being a monovalent acyclic hydrocarbon radical containingfrom 1 to 4 carbon atoms.

6. The process of claim 5, wherein the hydrocarbyl radicals are loweralkyl groups.

7. The process of claim 5, wherein one of the hydrocarbyl radicals is alower alkenyl group and the other is a lower alkyl group.

8. A process which comprises treating an oc,oL-Cll(lOWCfalkyl)-'y-aminomethylene-acetacetonitrile first with a solution of analkaline condensing agent, then with hydrogen sulfide, so as to form asolution of a 2-thio-3,3-di(lower alkyl)-4-oxo-1,2,3,4-tetrahydropyridine salt.

alltyl)-3-lower all enyl-4-oxo- References Cited in the file of thispatent UNITED STATES PATENTS 1,753,658 Kochendoerfer Apr. 8, 19302,686,786 Shaw Aug. 17, 1954 2,702,293 Hoffmann Feb. 15, 1955

1.A COMPOUND SELECTED FROM THE GROUP CONSISTING OF2-THIO-3,3-DIHYDROCARBYL - 4 - OXO-1,2,3,4-TETRAHYDROPYRIDINES, THEAMMONIUM AND ALKALI METAL SALTS THEREOF; SAID HYDROCARBYL BEING AMONOVALENT ACYCLIC HYDROCARBON RADICAL CONTAINING FROM 1 TO 4 CARBONCARBON ATOMS.
 5. A PROCESS WHICH COMPRISES CONDENSING ANA,A-DIHYDORCARBYL-ACETACETONITRILE WITH A LOWER FORMIC ACID ESTER IN THEPRESENCE OF AN ALKALINE CONDENSING AGENT TO PRODUCE THE CORRESPONDINGA,A-DIHYDROCARBYL-Y-HYDROXYMETHYLENEACETACETONITRILE, TREATING THELATTER WITH AMMONIA TO FORM A,A - DIHYDROCARBYL - Y-AMINOMETHYLENE-ACETACETONITRILE, CYCLIZING THE SAME BY MEANS OF ANALKALINE CONDENSING AGENT AND TREATING THE CYCLIZATION PRODUCT WITH ACOMPOUND SELECTED FROM A GROUP CONSISTING OF HYDROGEN SULFIDE AND AHYDROGEN SULFIDE PRODUCTING AGENT, TO PRODUCE A2THIO-3,3-DIHYDROCARBYL-4-OXO-1,2,3,4 - TETRAHYDROPYRIDINE; SAIDHYDROCARBYL BEING A MONOVALENT ACYCLIC HYDROCARBON RADICAL CONTAININGFROM 1 TO 4 CARBON ATOMS.